The present invention is within the field of encapsulating biologically active materials primarily in order to obtain a controlled, including sustained, release as well as increased uptake thereof as is desirable in many different technical fields, such as for instance to have a longer lasting or delayed effect of a pharmaceutically active material. More specifically the invention is based on a novel encapsulating or carrier material or system possessing a number of interesting features.
It has been known since the 1960""s that certain lipids and their analogues can form a variety of aqueous phases and that molecules that are lipophilic, hydrophilic or amphiphilic can be solubilized or dispersed in said phases. This is the basis for application of different lipid phases in drug delivery. The lamellar liquid crystalline phase and its dispersion as liposomes in excess of water is perhaps the best known example in this respect, and liposome encapsulated drugs exist on the market today. According to a more recent development cubic and reversed hexagonal phases have been utilized. A third type of carrier using lipids and lipid analogues is a microemulsion, which has recently been marketed as a carrier for cyclosporin. Furthermore, PCT/SE96/00893 can be referred to, which discloses the use of an L2 phase as a carrier for a cyclosporin.
The carrier systems referred to above are generally based on fatty acid esters of glycerol. As will be explained below the present invention is, however, based on a new carrier system, viz. a certain class of fatty acid esters of diglycerol. In this context it could be mentioned that fatty acids of polyglycerol have hitherto been used as functional additives in foods and in cosmetic formulations. However, to the best of our knowledge, the diglycerol esters upon which the present invention is based have never been disclosed or even suggested as carrier materials. More specifically, the characteristics of those diglycerol esters which by themselves form lipid water phases have never been utilized for controlled release of biologically active agents. Thus, in connection with food applications previous polyglycerol esters have been used to bind water in an oil during frying to stabilize an emulsion or to influence food texture. In connection with cosmetic formulations the previous polyglycerol esters have always been used in combination with other similar molecules, such as sugar esters or polyoxyethylene amphiphiles. Most applications concern stabilization of emulsion structure but sometimes also of gels, solutions and even solids (lipsticks). In other words, the common use of xe2x80x9cemulsifiers/stabilizersxe2x80x9d never is to achieve release of drugs or similar biologically active compounds.
As concerns diglycerol a detailed study thereof has been reported by Kumar et al. (JAOCS 66 (1989) 153). Diglycerol was first isolated from polymerized glycerol and then esterified with fatty acids. Mono- and diesters were then separated on a silica column. The surfactant properties were characterized by surface tension and studies of emulsion and foam stabilizations were made. However, nothing is mentioned about any formation of liquid aqueous phases or micellar solutions. The only report, to our knowledge, on formation of liquid crystalline phases in connection with polyglycerol esters is a report by Hemker (JAOCS 58 (1981) 114). The binary phase diagrams disclosed, however, merely involve triglycerol and octaglycerol esters and not the diglycerol esters. At all events, said reference does not disclose or suggest the advantageous properties of diglycerol esters utilized in our invention. Furthermore, the triglycerol and octaglycerol esters specifically referred to behave differently from our diglycerol esters.
As prior art reference can also be made to EP 0 455 391, which discloses polyglycerol fatty acid esters for use e.g. in the pharmaceutical field. However, the preparations disclosed therein are granulated, i.e. solid, compositions and do not have all valuable properties possessed by the liquid or liquid crystalline composition according the present invention. Furthermore, EP 0 455 391 is not specifically directed to any diglycerol esters or any valuable properties thereof as compared to other polyglycerol esters.
Thus, the present invention is based on the unexpected finding that certain fatty acid esters of diglycerol are highly efficient in solubilizing or dispersing biologically active materials, both as such and in combination with polar liquids. More specifically the present invention is based on the finding that the diglycerol fatty acid esters defined herein can form liquid or liquid crystalline lipid phases of those types which were referred to above in the opening part of our description. Firstly, these phases can be used to protect a biologically active material, for example against degradation in the gastric region, or against oxidation and hydrolysis, e.g. during storage. Furthermore, the uptake of the biologically active material can be improved, particularly penetration through mucous layers and membranes, for instance in oral delivery or in topical delivery, a great advantage being that the systems are bioadhesive. Other advantageous properties to be mentioned are non-irritant and non-toxic properties, which seem to be dependent, at least to some extent, on the length(s) of the hydrocarbon chains. In addition thereto, the previously known lipid phases can be accomplished in a simple way according to the present invention, viz. merely by varying the number or length of the hydrocarbon chains per molecule. In other words the phase properties can be varied successively in a very easy and advantageous way so as to control and optimize the desired delivery of for instance a particular drug.
As to the varying of phase properties it could be added that within the invention it is possible to accomplish diglycerol ester-water (or other polar liquid) phases ranging from the Lxcex1-type to the oil-continuous L2-type, the liquid crystalline phases cubic and reversed hexagonal phases lying therebetween. As a consequence thereof it is also possible, by a simple variation of the hydrocarbon chains, to adjust the composition of the system so as to be more or less close to any of these phase transitions. As an example of an interesting advantage in certain applications it could be mentioned that a composition or formulation just on the edge of, or adjacent to, a transition from lamellar to cubic phase represents fusion of cell membranes. Furthermore, if one is very close to a phase transition, a small shift in water content, for example at exposure to the aqueous gastric environment, can induce a fast release of an encapsulated drug through a desired phase transition. Even micellar solutions can be formed in cases of diglycerol esters of the shortest members of the fatty acids referred to. As far as we know, there are no carrier systems previously known which enable such extensive phase variations. Another interesting example is represented by the case where the composition is an L2 phase containing especially diglycerol monoester of fatty acid and which when contacted with water, or other polar liquid, is transformed into a liquid crystalline phase. Such a contact with water (or polar liquid) can take place in the human or animal body or outside the same.
Still another great advantage, which could not be expected from present knowledge about relation between chemical composition and lipid functionality, is the low chain melting temperature of our diglycerol esters as compared to for instance the corresponding monoglycerol ester. Thus, for instance formulations kept at 15xc2x0 C. with glycerol monoesters of tall oil fatty acids will contain crystals, whereas the corresponding diglycerol ester will not crystallize at all at said temperature. This is a very important characteristic for the intended uses of our novel compositions in that the general stability criterium for a drug formulation is no crystallization at 15xc2x0 C. to enable room temperature storage or use.